This proposal outlines experiments designed to grow larger crystals of the human histocompatibility antigen, HLA. To date, using a total of 5.5 mg of pure HLA-A2, A28, and B40, we have screened 230 crystallization conditions. Two crystal habits have been observed: 10 micron single crystals and larger polycrystalline stacks of plate-like crystals. X-ray diffraction patterns of the latter indicate an 81A x 68A lattice and resolution beyond 3A. With the larger quantities of tissue culture cells (and pure HLA) this proposal requests, we plan: (1) to explore more crystallization conditions; (2) to biochemically analyze present crystals to determine whether sialic acid charge micro-heterogeneity of this glycoprotein antigen limits crystal growth; (3) to improve the HLA, in collaboration with Professor J. L. Strominger's laboratory, to the level required for growing larger crystals. Our goal is to produce crystals of HLA suitable for determining its three-dimensional structure by X-ray crystallography. The three-dimensional structure of this polymorphic human membrane antigen would provide a framework for the rational analysis of primary sequence data from multiple allotypes. This would permit a detailed description of the sites of interaction with alloantisera and T cell receptors, as well as provide an apparoach to HLA-linked autoaggressive and neoplastic human diseases. Coupled with our work on the structures of the influenza virus surface antigen and proposed work on monoclonal Fab fragments, we hope to begin a detailed description of the molecular interactions in the H2 restricted cytolytic T cell response, and immunological recognition; and to provide insight into molecular and cell-cell recognition in general.